Downregulation of interleukin-12 (IL-12) responsiveness in human T cells by transforming growth factor-beta: Relationship with IL-12 signaling

Interleukin-12 (IL-12) is a cytokine that plays a central role in the contr ol of cell-mediated immunity. We have previously shown that transforming gr owth factor-beta 1 (TGF-beta) inhibitory effects on human primary allogenei c cytotoxicity and proliferative responses interfere with IL-12 pathway. Th e present study was undertaken to further elucidate the biochemical basis o f the functional interaction between these two cytokines and to define the site of TGF-beta action on the signaling pathway activated by IL-12, Our da ta indicate that TGF-beta induced an inhibition of interferon-gamma (IFN-ga mma) production without affecting the IL-12R beta 1 and IL-12R beta 2 subun its mRNA expression by activated T cells. We further show that TGF-beta has a significant inhibitory effect on the early signal transduction events fo llowing interaction of IL-12 with its receptor on activated T cells, result ing in the inhibition of both JAK2 and Tyk2 phosphorylation. In addition, T GF-beta was found to significantly inhibit IL-12-induced phosphorylation of the STAT4 transcription factor. Electrophoretic mobility shift assay indic ated that TGF-beta induced a decrease in IL-12-induced STAT4 DNA binding ac tivity in T lymphocytes. This study suggests that TGF-beta influences IL-12 responsiveness at least in part by inhibiting early signaling events essen tial to gene induction in IL-12-activated T cells. (C) 1999 by The American Society of Hematology.